PROJECT SUMMARY Prenatal and postnatal childhood exposure to metals, essential and non-essential, is ubiquitous via dietary and environmental sources. Heavy metals, including lead and methylmercury, are well characterized as potent neurotoxicants, associated with lower cognition and poor learning abilities. Yet, our understanding of the neurotoxicity and joint impact of many other common prenatal and postnatal metal exposures remains extremely limited. Even less is known about the combined impact of exposure to multiple metals during fetal development or postnatal exposure during early childhood, or the influence of other environmental mixtures such as nutrients, which may have shared sources, on the neurodevelopmental effects of metals. To address this significant gap, our long-term goal is to quantify the neurocognitive impact of ubiquitous prenatal and postnatal environmental mixtures and identify cord blood DNA methylation biomarkers that can reconstruct prenatal environmental exposures and predict future neurocognitive development in children. We will test if objective measures of key prenatal maternal nutrients, such as folate, vitamin B12 and essential metals attenuate or mitigate the neurotoxicity of metal mixtures. To accomplish this goal, we will leverage resources from an established U.S. pre-birth cohort, Project Viva. In this cohort, we have measured concentrations for 14 prenatal maternal metals in the first trimester of pregnancy and blood samples collected in early-childhood (~3 years) ready for metal testing as well as ready to use genome-wide cord blood DNA methylation screens. Children have been followed prospectively and undergone detail testing for neurodevelopment in early (~3 years of age) and mid-childhood (~7 years). We hypothesize that prenatal maternal 1st trimester and postnatal early childhood neurotoxic metal mixtures are associated with poor neurodevelopment in early and mid-childhood (Aim 1), and that prenatal first trimester maternal plasma folate, vitamin B12 and blood concentration of essential metals protect against prenatal metal mixture neurotoxicity (Aim 2). We also hypothesize that DNA methylation marks measured in umbilical cord blood at birth can reconstruct prenatal exposure to metals (Aim 3.a) and that cord blood DNAm marks predict future neurocognitive development in early and mid-childhood (Aim 3.b). By testing longitudinal associations in a large cohort of children with detail cognitive assessments as well as objective biomarkers of metals and nutrients, we will overcome limitations currently faced by existing studies testing few exposures simultaneously. We will use novel statistical methodology to model prenatal and postnatal environmental mixtures and machine learning algorithms to build epigenetic predictors of exposure and neurodevelopment. This research will provide a comprehensive quantification of the cognitive burden of prenatal and postnatal mixtures, the development of biomarkers of exposure and neurodevelopment and the identification of potential prenatal nutritional intervention strategies.